Atherosclerosis is a chronic cardiovascular disease common in patients exhibiting hypercholesterolemia[1]. The number of adults with diagnosed heart disease has been estimated to be 26.6 million (11.3%) in the US[2], with more than half of those patients are associated with or are potentially causal with respect to atherosclerotic disease. Prevention and early diagnosis of atherosclerotic disease complications is a top priority in modern medicine[3], as early lifestyle and medical interventions can slow the rate of atheroma development and avert adverse cardiovascular sequelae. Early stage diagnosis is challenging, however; symptoms often become clinically evident only at late stages where complete prevention is no longer viable[4]. As vascular disease progresses, the inflammatory and remodeling process also evolves, and the plaque can become unstable or vulnerable to erosion or rupture, which in turn initiates life-threatening thrombotic outcomes. The penultimate pathological event, plaque rupture, is identified due to thrombogenic processes and immune cell infiltration[5]. Histological changes in a vulnerable plaque such as thin fibrous cap, intraplaque hemorrhage and/or a lipid-rich necrotic chore (LRNC) are present in ˜80% of ruptured plaques, but such manifestations require a prolonged and variable time for progression[6].
Cardiovascular inflammation[7] and remodeling due to atherogenic progression[8] have also been identified as leading causes of plaque instability, despite incomplete understanding of these complex process[9]. ApoE−/− mouse model on HFD exhibits rapid development of atheromatous plaques[10], with features and stages that mirror those of the human disease[11]. Early stages of atherosclerosis typically include altered homeostasis and activation of the vascular endothelium, typified by a loss of nitric oxide generation and increased expression of chemokines and adhesion molecules[12], which is evident in the ApoE−/− model[13]. The role of T cells and monocytes recruited to the plaques and perivascular regions have been studied extensively in the vascular immune response, but the ability to identify intraplaque presence and extent of specific leukocyte subtypes is mostly limited to invasive and/or post-mortem or post-resection imaging[14-16]. The role of intraplaque neutrophil accumulation has been recently identified as a focus point in atherosclerotic plaque vulnerability[17]. Elevation of typical biomarkers for disease progression is exploited by molecular imaging[18], which is limited at the same lime because of the low specificity of current diagnostic tools.
DANBIRT was developed by chemical repurposing of BIRT 377, which is a specific therapeutic agent for leukemia and lymphoma, as it targets LFA-1 expressed on both B and T-cells[19]. Developed targeted ligand, DANBIRT, is a small non-ionic compound that acts as an allosteric inhibitor of LEA 1[20]. The importance of LFA-1 is critical for the initiation and impulse of a vascular immune response to injury[21]. LFA-1 is involved in specific interaction with Intracellular Adhesion Molecule-1 (ICAM-1) in endothelial cells by which transmigration is achieved[22]. Radiolabeling DANBIRT using 111In (FIG. 1) allows co-localization of the radiopharmaceutical in cardiovascular and immune tissues[23].